Reactionso fpyridazine san dpyridazin e1-oxide s withnitrogen-containin g nucleophiles 1185 Ditproefschrif tme tstellinge nva nDimb yEelc oKlinge , doctorandusi nd echemie ,gebore nt eGroot-Ammer so p4 jul i1942 , isgoedgekeur ddoo rd epromotor ,dr.H.C.va nde rPlas ,hoogleraa r ind eorganisch echemie . Derecto rmagnificu sva nd eLandbouwhogeschool , J.P.H.vande rWan t Wageningen,29maar t197 6 Y\n <9zo \ 6^2- D.E.Klinge Reactionso f pyridazinesan dpyridazin e 1-oxides with nitrogen-containing nucleophiles Proefschrift terverkrijgin gva nd egraa dva n doctori nd elandbouwwetenschappen , opgeza gva nd erecto rmagnificus , dr.ir.J.P.H.vande rWant ,hoogleraa ri nd evirologie , inhe topenbaa rt everdedige n opwoensda g2 jun i197 6de snamiddag st evie ruu r ind eaul ava nd eLandbouwhogeschoo lt eWageninge n fSrt *-/0¥'3l 'L-0 3 • ,rr,.rir... T: —* 7 A//J gz&/ 6s Ay Stellingen 1.D edoo rTurne re nCheesema ngegeve ngrafie kwaari nd e C-substituenteffee - tenva n2-gesubstitueerd e pyrazinenzij nuitgeze ttege ndi eva nmono-gesub - stitueerdebenzenen ,correleer tnie tme td edoo rhe ngemete nwaarden . C.J.Turner enG.W.H.Cheeseman , Org.Magn.Reson.6_ ,66 3 (1974). 2. Heti sonvoldoend ebeweze nda tnematicid ewerkin gka nworde ntoegeken daa nd e uitd eHeleniu mhybrid e "MoerheimBeauty "ge'isoleerd eve'rbindin g2,3-dihydro - -2-hydroxy-3-methyleen-6-methylbenzofuraan. F.J.Gommers,Proefschrift ,Groninge n1973 . 3.D eamino-dehalogenerin gva n2-chloor-3,6-difenylpyrazin e kanvolgen see nan - dermechanism everlope nda nvoorgestel dword tdoo rLon te tal . P.J.Lont,H.C.va nde rPla se nA.va nVeldhuizen , Recl.Trav.Chim.Pays-Ba s 92_,70 8 (1973). 4.O pgron dva nd evermeld e H-NMRgegeven si snie tt ebewijze nda t6-aryl-4,5 - dibenzyl-3-oxo-2,3,4,5-tetrahydropyridazinen gevormdworde ni nd ereacti eva n 6-aryl-2,3-dihydro-3-oxopyridazinen metbenzylmagnesiumchloride . F.G.Baddar,N.Lati fe nA.A.Nada , J.IndianChem .Soc . 1974,618 . 5.D econclusie sdi edoo rLevin ee nBieh lzij ngetrokke nui thu nexperimente n terbestuderin gva nhe teffec tva nd ealkalianione ni nd ereacti eva no-chloor - tolueenme talkaliamiden ,zij nonvoldoend egefundeerd . R.Levinee nE.R.Biehl , J.Org.Chem.40 ,183 5 (1975). 6.Bi jd everklarin gva nhe tverschi li nreductiesnelhei dva n 2-jood-nitrobenzeen en2-joodpyridin e door2-methylpiperidine ,word tte nonrecht ehe tverschi li n snelheidva nd eamino-dejoderin gbuite nbeschouwin ggelaten . E.Farina,L.Nucci ,G.Biggi ,F.De lCim ae nF.Pietra , TetrahedronLett .1974 ,3305 . 7.He tmechanism eva nd eautoxidati eva n 5-methyl-6,7-difenyl-5,6,7,8-tetrahydro- pterinevoorgestel ddoo rJongeja ne tal. ,i songeschik tal smode lvoo rd ebio - logischewerkin gva nd eco-facto r5-methyl-tetrahydro-foliumzuur . J.A.Jongejan,H.I.X.Mage r enW.Berends , Tetrahedron 31,53 3 (1975). 8.D egroeiend erelati eva nhe thoge rberoepsonderwij sto the twetenschappelij k onderwijsmoe tnie tal sargumen tgebruik tworde no m "lichamelijkeoefening " alsverplich talgemee nva kvoo rhe thoge rberoepsonderwij sa ft eschaffen ,maa r om "lichamelijkeoefening "al sverplich talgemee nva kvoo rhe twetenschappelij k onderwijsi nt evoeren . Wetsontwerpto twijzigin gva nartike l 16,derd eli d Weto phe tvoortgeze tonderwij s (Stb.1967 , 387). D.E.Kling e Reactionso fpyridazine san dpyridazin e 1-oxideswit hnitrogen-containin gnucleophile s Ternagedachteni saa nmij nvade r Aanmij nmoede r Ireen Michiele nDaa n Contents Introduction 7 PaperI :"Evidenc efo ra 4,5-didehydropyridazine inth eaminatio no f4-halogenopyridazine s withpotassiu mamid ei nliqui dammonia " 14 Paper II :"O nth eexistenc eo f4,5-didehydropyridazine " 17 Paper III :" H-NM Rinvestigation so na-adduc tformatio n ofpyridazine ,o fpyridazin e 1-oxidean dsom e ofit sderivative swit hammonia .A ne wsubsti ­ tutionmechanism " 20 Paper IV :" C-NMRdat ao fpyridazine san dsom eo fthei r covalentaminatio nproducts " 24 PaperV :"Conversio no f 4-amino-3-halogenopyridazines intopyrazole san do f 4-amino-3,6-dihalogeno- pyridazinesint o1,2,4-triazoles " 27 Discussion 31 Samenvatting 36 Introduction Therei sa prevailin g interest inth eLaborator yo fOrgani cChemistry , AgriculturalUniversit yWageningen ,i nth estud yo fth ebehaviou ro fhalogeno - 15-18 azaaromaticsi nreaction swit hnucleophile s (potassiumamid e 2-14 ammonia 19—22 23 Inth emonocycli csystem s lithiumpiperidid e ,potassiu mt-butanolat e ) especiallyth ereaction so fderivative so fpyridin e ,pyrimidin e and pyrazine withpotassiu mamid ei nliqui dammoni awer estudie dextensively . Fromthes estudie sth emechanisti cpictur ei semergin gtha ti ngenera lhalo - genopyridinesar emor eincline dt osubstitutio nreaction s without ringopenin g thanhalogenopyrimidine san dhalogenopyrazines ,whic hpreferentiall yunderg o substitutionsinvolvin ga nopen-chai ncompoun da sintermediate . Inprincipl eth enucleophili csubstitutio nreaction swhic har efoun dt o occurwhe nhalogenopyridine sar etreate dwit hpotassiu mamid ei nliqui dammoni a andwhic hd ono tinvolv ea nopen-chai nintermediat eca nb edivide d intothre e maincategorie s (seeSchem e 1): a.S IAEJ (theformatio no fa a-intermediat e byAdditio no fth eamid eio no nth erin gcarbo nato mbearin gth ehaloge natom , followedb yEliminatio no fth ehaloge n ion);b .S JAEJ-cinesubstitutio n (the attacko fth eamid eio ntake splac eo na rin gcarbo nato mt owhic hth ehaloge n atomi sno tattached ,followe db yprotonatio nan dth elos so fhydroge nhalide ) and£ .S (EAJ (abase-catalyse d Eliminationo fhydroge nhalid eformin gth e intermediarydidehydropyridin e followedb yAdditio no fammonia) .Fro mth e last-mentionedreactio na mixtur eo f3 -an d4-aminopyridin eresults . NH2 Therei sa ninterestin gdifferenc ei nth echemica lbehaviou ro fth ehalogeno - pyridinesan dth ehalogen oderivative so fth ediazines ,pyrimidin ean dpyrazine . Asalread yindicated ,th elatte rpreferentiall ysho wsubstitutio nwit hrin g openingo nreactio nwit hpotassiu mamid ei nliqui dammonia .Thi si sdu et oth e 24 facttha ti ngenera ldiazine seasil yfor ma-adduct s withth eamid eio na ta ringcarbo nato mwhic hi sno tsubstitute db ya haloge nato m (seefo rexampl e 8d 9ab 1 structurx. e (2,->)xi •n Schem „^ eo %2) .! „H-NM» m.T,R / » 0g,17,18" a an,d13 „C-NM„ m9Rc spectroscopy presentgoo devidenc efo rth eformatio no fthes eadducts .I ti so finteres tt o notetha tth eopen-chai nintermediat ewhic hi sforme dafte rrin gopenin gca n undergoa rin gclosur eleadin gt oth e same ringsyste ma si nth estartin g substance16'7'8'17. Experimentalevidenc efo rthes eso-calle ddegenerat erin gtransformation s wasobtaine db ya nextensiv estud yo fth e N-scramblingi nth ereactio npro - 15 duct^.4. sobtaine u. • * dwhe u nf | N«jl-halogenopyrimidine v,i •-.* • 7bcde,8,16b,17,2s 2 . anfl5d J|_ N j- lOcde halogenopyrazines aretreate dwit hpotassiu mamid ei nliqui dammonia . Seefo rexampl eth econversio no f4-chloro-6-phenylpyrimidin e (1)int o4-amino - 6-phenylpyrimidine (4)(Scheme2 )involvin ga nAdditio no fth eNucleophil e (at C(2)),Rin gOpenin g (into (3))an dRin gClosure .On erefer st othi ssubstitutio n mechanisma sa nS„(ANRORC)-mechanis m. TH II — H C X C6H5 H^^tf'^CeHs "X=N '^CeH s ^N^^BMS H2N » 12 3 4 SCHEME 2 Aver yimportan tfeatur eo ftnes ereaction si stha tafte radditio nan drin g openingb y fissiono fa carbon-carbo nbond ,a nopen-chai nintermediat ei sforme d which,i fappropriat esubstituent sar epresent ,ca nunderg oa rin gclosur elead ­ ingt oa different ringsyste mtha ntha to fth estartin gsubstanc e ' ' ' ' Forexampl e4-chloro-2-phenylpyrimidin e (5)react swit ha namid eio nt ogive , viath ea-adduc t (6),th eopen-chai nintermediat e (7).Rin gclosur ethroug ha n internalnucleophili cattac ko fth eamidine-nitroge no nth eunsubstitute dcarbo n atomo fth etripl ebon dresult si nth es-triazin e derivative (8)(Scheme3 ) 25-28 CH3 ^C=CH 21 *y H5C6 ^N=c' HSCS^N ^NH2 SCHEME 3 Carbon-carbonbon dfissio ni nth eazaheteroaren eha sals obee nobserve dwhen , besidesa haloge natom ,th eheterocycl econtain sa substituen twhic hca neasil y bedeprotonate db yth eamid eion ,fo rexampl ea namino -o rhydroxy 1group .I n thatcas eth eheterocycli crin gbecome snegativel ycharge dthroug hmesomeris m andtherefor emake sth erin gles ssusceptibl et onucleophili caddition . Interestingexample so freaction si nwhic hthi scarbon-carbo nbon d fissionoccur s 29 areth erin gcontractio no f3-amino-2-bromopyridin e (9)int o3-cyanopyrrol e (10) ando f5-amino-4-chloro-2-phenylpyrimidin e (11)int o 4(5)-cyano-2-phenylimidazole 30 (12) (Schem(Scheme 4)4). _ - ^ NH2 0 A NTH[Q* NH2 * Kll ©X-CN HC^H II N=C< Br oH 10 CI NH2 N^Sr H5CkJ6 ^^N HsCe SCHEME 4 11 12 Theexperience sobtaine di nth epyrimidin ean dpyrazin efiel dinduce du st o studyth echemica lbehaviou ro fth ethir drepresentativ eo f'th ediazine si.e . thepyridazin e .Ou rinteres twa sespeciall yconcentrate do nth eproble m whetherhalogenopyridazin ederivative si nreaction swit hpotassiu m amidei n liquidammoni aar emor eincline dt osubstitutio nreaction sb yS [AE] orS |EA] processeso rt oadditio nreaction sbein gfollowe db yrin gopening .Calculation s 32 usingth eExtende dHucke lTheor yindicat e that4,5-didehydropyridazin e (13)i s a farmor establ eintermediat etha nth ewell-establishe d 3,4-didehydropyridine, sotha ti tseeme dver ychallengin gt oestablis hth eoccurrenc eo fthi sdidehydro - pyridazine. Therear esevera lreaction sreporte di nth eliteratur ei nwhic hdidehydro - pyridazinesar eadvance dbu twher ethei rexistenc ei sno treall yproven . 33 .Kauffmanne tal . proposedth e "4,5-didehydropyridazine (14)"a sintermediat e inth ereactio no f l-methyl-2-phenyl-4-X (X=C1,Br) -an d-5- X (X=Br)-pyridazine- 3,6-dionewit hpiperidine .A nisomeri cmixtur eo f4 -an d 5-piperidinopyridazines wasobtained ,bu tsinc ethei rrati oi sno tindependen to fth enatur eo fth e 10 halogenatom ,a possibl esimultaneou soccurrenc eo fa nS [AEj-substitution anda nS j_AEJ-cinesubstitutio nca ncertainl yno tb eexcluded .